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Modeling Oral-Esophageal Squamous Cell Carcinoma in 3D Organoids
Published on: December 23, 2022
CD155 Cooperates with PD-1/PD-L1 to Promote Proliferation of Esophageal Squamous Cancer Cells via PI3K/Akt and MAPK
Xiyang Tang1, Jie Yang1, Anping Shi2
1Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, 569 Xinsi Road, Xi'an 710038, China.
Background:
Esophageal cancer is still a leading cause of death among all tumors in males, with unsatisfactory responses to novel immunotherapies such as anti-PD-1 agents. Herein, we explored the role of CD155 in esophageal squamous cell cancer (ESCA) and its underlying molecular mechanisms.
Methods:
Publicly available datasets were used for differential gene expression and immune infiltration analyses, and their correlation with patient survival. A total of 322 ESCA and 161 paracancer samples were collected and evaluated by performing immunohistochemistry and the H score was obtained by performing semiquantitative analysis. In vitro transfection of ESCA cell lines with lentivirus vectors targeting CD155 was performed to knockdown the protein. These cells were analyzed by conducting RNA sequencing, and the effects of CD155 knockdown on cell cycle and apoptosis were verified with flow cytometry and Western blotting. In addition, in vivo experiments using these engineered cell lines were performed to determine the role of CD155 in tumor formation. A small interfering RNA-mediated knockdown of Nectin3 was used to determine whether it phenocopied the profile of CD155 knockdown.
Results:
CD155 is highly expressed in ESCA tissues and is positively associated with PD1, PDL1, CD4, IL2RA, and S100A9 expression. Furthermore, CD155 knockdown inhibited ESCA cells' proliferation by impairing the cell cycle and inducing cell apoptosis. Bioinformatics analysis of the gene expression profile of these engineered cells showed that CD155 mainly contributed to the regulation of PI3K/Akt and MAPK signals. The downregulation of Nectin3 expression phenocopied the profile of CD155 knockdown.
Discussion:
CD155 may cooperate with PD-1/PD-L1 to support ESCA proliferation in ways other than regulating its underlying immune mechanisms. Indeed, CD155 downregulation can impair ESCA cell pro-cancerous behavior via the inhibition of the PI3K/Akt and MAPK signaling pathways. Moreover, Nectin3 may be a ligand of CD155 and participate in the regulation of ESCA cells' proliferation. Hence, the inhibition of CD155 may enhance the therapeutic effect of anti-PD-1 immunotherapies in ESCA.
Insights
CD155 drives esophageal squamous cell cancer (ESCA) growth by affecting cell cycle and apoptosis. Inhibiting CD155 may improve anti-PD-1 immunotherapy effectiveness in ESCA patients.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Esophageal cancer remains a significant cause of cancer-related mortality in males.
- Current immunotherapies, like anti-PD-1 agents, show limited efficacy in esophageal squamous cell cancer (ESCA).
- The role of CD155 in ESCA pathogenesis requires further investigation.
Purpose of the Study:
- To explore the function of CD155 in esophageal squamous cell cancer (ESCA).
- To elucidate the molecular mechanisms by which CD155 influences ESCA progression.
- To assess the potential of targeting CD155 to enhance anti-PD-1 therapy outcomes.
Main Methods:
- Analysis of publicly available datasets for gene expression and immune infiltration.
- Immunohistochemistry on ESCA and adjacent normal tissues.
- In vitro studies involving CD155 knockdown in ESCA cell lines using lentivirus vectors.
- RNA sequencing, cell cycle, apoptosis assays, and Western blotting.
- In vivo tumor formation experiments and Nectin3 knockdown studies.
Main Results:
- CD155 is upregulated in ESCA tissues and correlates with PD1, PDL1, CD4, IL2RA, and S100A9 expression.
- CD155 knockdown suppressed ESCA cell proliferation by inducing cell cycle arrest and apoptosis.
- Bioinformatics analysis indicated CD155 regulates PI3K/Akt and MAPK signaling pathways.
- Downregulation of Nectin3 mimicked the effects of CD155 knockdown.
Conclusions:
- CD155 may promote ESCA proliferation independently of PD-1/PD-L1 immune regulation.
- CD155 inhibition impairs ESCA cell growth by suppressing PI3K/Akt and MAPK pathways.
- Nectin3 is a potential CD155 ligand involved in ESCA cell proliferation.
- Targeting CD155 could potentially augment the efficacy of anti-PD-1 immunotherapies for ESCA.
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